rs587776441

Positions:

• chrM-1644-G-A
• chrM-1644-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2_Supporting PS4_Moderate PS3_Supporting PM5_Supporting PP1 PP3

This summary comes from the ClinGen Evidence Repository: The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID:32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID:15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID:24691472). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA913163370/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-TV ENST00000387342.1 non_coding_transcript_exon
• Scores: Mitotip Uncertain 13
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 O:1 Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome
• Conservation: PhyloP100: 0.980

Genes affected

MT-TV (HGNC:7500): (mitochondrially encoded tRNA valine)

TRNV (HGNC:):

MT-RNR2 (HGNC:7471): (mitochondrially encoded 16S RNA) Enables G protein-coupled receptor binding activity; protein self-association; and receptor antagonist activity. Involved in several processes, including leukocyte chemotaxis; negative regulation of cell death; and negative regulation of neuroinflammatory response. Located in several cellular components, including mitochondrion; perinuclear region of cytoplasm; and sperm midpiece. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNV	TRNV.1	n.43G>A		non_coding_transcript_exon_variant	1/1
RNR2	RNR2.1			upstream_gene_variant
RNR1	RNR1.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT-TV	ENST00000387342.1	n.43G>A		non_coding_transcript_exon_variant	1/1
MT-RNR2	ENST00000387347.2			upstream_gene_variant
MT-RNR1	ENST00000389680.2			downstream_gene_variant

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56431

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56431

Mitomap

Leigh-Syndrome-/-HCM-/-MELAS,Adult-Leigh-Syndrome

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Juvenile myopathy, encephalopathy, lactic acidosis AND stroke Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine	Jul 12, 2019	The NC_012920.1:m.1644G>A variant in MT-TV gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PS5, PP3 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Dec 10, 2021

The m.1644G>A variant in MT-TV was reviewed by the Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel as part of the variant pilot for mitochondrial DNA variant specifications (McCormick et al., 2020; PMID: 32906214). This variant has been reported in 7 individuals with primary mitochondrial disease with variable features including cardiac (hypertrophic cardiomyopathy, LBBB); neurologic (neurodegeneration/dementia, stroke-like episodes, recurrent encephalopathy, epilepsy, ataxia, dystonia, Parkinsonism, mood disorder/disturbances, fatigue, muscle weakness, exercise intolerance, neuropathy, cognitive impairment, developmental regression); audiologic (bilateral sensorineural hearing loss); renal (cystic renal disease); GI (severe GI dysmotility, cachexia); and endocrine (diabetes) concerns as well as lab abnormalities (elevated blood and CSF lactate, elevated CK), and brain imaging abnormalities (atrophy, basal ganglia lesions, MRS lactate peak); with heteroplasmy levels in multiple tissues ranging from 85% to homoplasmy (PS4; PMIDs: 15320572, 23847141, 18314141, 21986556, 24691472). This variant heteroplasmy level segregated with severity in 2 family members from 1 family (PP1; PMID: 15320572). This variant is located at the same position as another variant associated with mitochondrial disease, m.1644G>T (PM5_supporting). This variant is absent in the GenBank data set and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant impacts the function of this tRNA, as does HmtVar with a score of 1 (PP3). Cybrid studies supported the functional impact of this variant (PS3_supporting; PMID: 24691472). In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel as of August 20, 2020. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PS3_supporting, PM2_supporting, PM5_supporting, PP1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Uncertain	13
Hmtvar	Pathogenic	1.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776441; hg19: chrM-1646;